This application is a 371 of PCT/US99/13481 filed Jun. 15, 1999.
The present invention relates to a process for preparing a pharmaceutical bulk material having more uniform dissolution in water, in particular, uniform dissolution of cefaclor bulk material.
Cefaclor (3-chloro-7-D-(phenylglycinamido)-3-cephem-4-carboxylic acid) is a semi-synthetic, second-generation, cephalosporin antibiotic. Cephalosporins exert their antibacterial activity by reacting with and thereby inactivating one or more of the penicillin-binding proteins located in the bacterial cell wall. Cefaclor is active against a wide range of commonly found pathogens, including S. aureus, xcex2-haemolytic streptococci pneumonococci, Haemophilus influenzae, E. coli, Klebsiella pneumoniae and Proteus mirabilis. The preparation of cefaclor is described in German Patent No. 2,408,698; U.S. Pat. No. 3,925,372; and Chauvette, R. R. and P. A. Pennington, J. Med. Chem, 18, 403 (1975).
Pharmaceutical forms currently available for oral administration of cefaclor include capsules, retard tablets and suspension (both in vial and sachet form). To be useful as a capsule, the USP standard for cefaclor capsules requires at least 80% (Q) of the capsule to dissolve in water in 30 minutes. The dissolution rate is dependent upon the solubility of the active ingredient(s) as well as the excipients used in the formulation and ingredients used in the formation of the capsule. Applicants have observed that capsules prepared from freshly prepared cefaclor monohydrate bulk materials do not consistently meet the USP standard; however, capsules prepared from aged cefaclor monohydrate bulk materials more consistently meet the USP standards. Although acceptable product can be produced from aged materials, the aging process causes several disadvantages. For example, the material is not available for use over an extended period of time, storage costs, and lot to lot variability over time. Therefore, there is a need to provide a process that produces capsules having more uniform and consistent dissolution rates without having to age the bulk active material.
The present invention provides a process for producing cefaclor crystalline bulk form having a dissolution rate in a capsule of xe2x89xa780% in water in 30 minutes at 37xc2x0 C. which comprises the steps of (i) providing cefaclor material having a dissolution rate in a capsule of  less than 80% in water in 30 minutes at 37xc2x0 C.; and (ii) reducing the water content of the cefaclor material to produce a cefaclor form having a water content xe2x89xa62%. The material produced having a water content xe2x89xa62% may optionally be rehydrated to a water content from about 3.0% to about 6.5%. The cefaclor material having a dissolution rate in a capsule of  less than 80% in water in 30 minutes at 37xc2x0 C. may be characterized by: the presence of a near infrared reflectance (NIR) absorbance at 5798 cmxe2x88x921 (1725 nm) either initially or within 5 minutes after the addition of water to the sample (i.e., NIR onset time  less than 5 minutes); having a non-homogenous water content (e.g., lots containing residual dihydrate starting materials); or agglomerates upon addition of water.
In another embodiment of the present invention, a process for producing cefaclor crystalline bulk form having a dissolution rate in a capsule of xe2x89xa780% in water in 30 minutes at 37xc2x0 C. which comprises the steps of (i) providing cefaclor dihydrate; and (ii) reducing the water content of the cefaclor dihydrate to produce a cefaclor form having a water content xe2x89xa62%.
In yet another embodiment of the present invention, a process is provided for producing cefaclor crystalline bulk form having a dissolution rate in a capsule of xe2x89xa780% in water in 30 minutes at 37xc2x0 C. which comprises the steps of (i) providing cefaclor bulk material having a dissolution rate in a capsule of  less than 80% in water in 30 minutes at 37xc2x0 C.; and (ii) adding xe2x89xa70.05% of cefaclor related substances.
Crystalline cefaclor bulk materials and capsules prepared therefrom having a dissolution rate in a capsule of xe2x89xa780% in water in 30 minutes at 37xc2x0 C. prepared by the processes described above are also provided. One can also use the crystalline cefaclor bulk materials prepared by the processes described herein in other oral formulations such as tablets and liquid suspensions.
As used herein, xe2x80x9ccefaclor crystalline bulk formxe2x80x9d or xe2x80x9ccefaclor crystalline bulk materialxe2x80x9d refers to a mixture of a non-stoichiometric cefaclor monohydrate and anhydrous cefaclor.
xe2x80x9cNIR onset timexe2x80x9d refers to the time between addition of water to a cefaclor sample and the observation of an absorption peak at about 5798 cmxe2x88x921 (1725 nm) as measured by Near-Infrared Reflectance Spectroscopy (NIRS). Depending upon the particular instrument used, the exact peak measurement may vary within the standard deviation established for that particular instrument.
xe2x80x9cCefaclor related substancesxe2x80x9d refers to degradation products of cefaclor that are structurally related to the pharmaceutically active cefaclor compound. For example, related substances include compounds such as the xcex942-isomer of cefaclor, the decarboxylated derivative of cefaclor, and other similar degradation products.